1. Field of the Invention
The present invention relates to compounds of Formula I that are useful as conformational modulators of a protein kinase. The compounds are also useful for inhibiting a protein kinase. The present invention also relates to a composition comprising said compound, and various methods of using a compound of Formula I to treat a protein kinase-mediated condition or inhibit a protein kinase.
2. Background Art
Protein kinases play a vital role in the functioning of cellular processes. The activation and deactivation of particular molecular pathways are often controlled by the phosphorylation or dephosphorylation of one or more proteins.
For example, mitogen activated protein kinases, such as p38 kinase, are activated in response to various stress stimuli, including, but not limited to, proinflammatory cytokines, endotoxin, ultraviolet light, and osmotic shock. Four isoforms of p38 have been described. The α and β forms are expressed in inflammatory cells and are considered to be key mediators of TNF-α production. Inhibition of the enzymes p38α and β in cells results in reduced levels of expression of TNF-α, and such inhibitors are effective in animal models of inflammatory disease.
Numerous small molecule inhibitors of p38 are known in the art. These compounds are thought to exert their effects by binding discrete locations on the surface of a p38 kinase. For example, certain p38 inhibitors block the production of TNF-α and IL-1; others can directly interfere with many of their secondary biological effects.
A protein can exist in a number of different conformations. These conformations can differ from each other in various ways. For example, the conformations can have different specific amino acids existing in various three-dimensional configurations. On a more global perspective, a protein can exist in different configurations of its overall tertiary structure. For example, certain proteins can exist in both an “open” conformation and a “closed” conformation.
A compound that can stabilize the open conformation of a protein kinase would be valuable as a tool for studying the action of kinases. Such a compound would also be useful for many reasons, for example, as a tool for drug discovery.